Liver and metabolism L10

Question 1

Type 1 insulin dependent diabetes

Answer 1

Cannot survive without insulin

Mainly young, but increasingly observed later in life

Ketosis may lead to death

Autoimmune destruction of B cells of islets of Langerhans

Sometimes follows viral infections (mumps, rubella, measles)

Treatment: insulin injections

Question 2

Classical symptoms of type 1 diabetes

Answer 2

Thirst, tiredness, weight loss

Polyuria

Hyperglycaemic coma

Question 3

Metabolic consequences of type 1 diabetes

Answer 3

Blood insulin levels low despite high blood glucose, whereas glucagon levels are raised

Insulin: glucagon ration cannot increase even when dietary glucose enters from the gut

Low insulin: glucagon ration leads to induction of catabolic enzymes and repression of anabolic enzymes

Question 4

Type 1 diabetes- the liver

Answer 4

Liver remains gluconeogenic because of high glucagon

Lactate and amino acids such as alanine from protein breakdown are main substrates for glucose production hence muscle wasting

Glycogen synthesis and glycolysis inhibited

Fatty acids from lipolysis enter liver and provide energy for gluconeogenesis

Excess acetyl CoA from fatty acid oxidation converted to ketone bodes and if not used sufficiently can rapidly lead to ketoacidosis due to accumulation of ketone bodies and H+ in blood

Question 5

Type 1 diabetes- the muscles

Answer 5

Relatively little glucose entry into muscle and peripheral tissues because of insulin lack- hyperglycaemia

Fatty acid and ketone body oxidation used as major source of fuel

Proteolysis occurs to provide carbon skeletons for gluconeogenesis leading to muscle wasting

Question 6

Type 1 diabetes- adipose tissue

Answer 6

High glucose concentrations in plasma but uptake of glucose diminished by loss of insulin

Low insulin: glucagon ration enhances lipolysis leading to continuous breakdown of triacylglycerol and release of fatty acids and glycerol into blood stream to support energy production in peripheral tissues and gluconeogenesis in the liver

Question 7

Type 1 diabetes- plasma and urine

Answer 7

Constant production excess glucose while utilising less leads to hyperglycaemia

Glucose concentration exceeds renal threshold, excreted in urine with loss of water and development of thirst

Fatty acid synthesis greatly diminished; VLDL secreted by liver and chylomicrons entering from gut cannot be metabolised properly as expression of lipoprotein lipase is regulated by insulin

Results in hypertriglyceridaemia and hyperchylomicronaemia and susceptibility to cv event

Question 8

Short term consequences

Answer 8

Hyperglycaemia and ketoacidosis characteristics of type 1 diabetes

Hyperosmolar hyperglycaemic state (non ketotic hyperosmolar coma) characteristc of type 2 diabetes

Question 9

Long term life threatening consequences of diabetes

Answer 9

Predisposition to CV disease and organ damage

Retinopathy- cataracts, glaucoma and blindness

Nephropathy

Neuropathy

Question 10

High concentration of glucose results in

Answer 10

Generation of ROS

Osmotic damage to cells

Glycosylation leading to alterations in protein function

Formation of advanced glycation end products which increase ROS and inflammatory protein

Question 11

Two major tests for diagnosing diabetes

Answer 11

Fasting blood glucose levels

Glucose tolerance test

Question 12

Fasting blood glucose levels test

Answer 12

After overnight fast a blood glucose value of 126mg/dl and above on at least two occasions indicates diabetes

Question 13

Glucose tolerance test

Answer 13

Performed in morning after and overnight fast

Fasting blood sample is removed and subject drinks ‘glucola’ drink containing 75g glucose

Blood glucose then sampled at 20 min, 1 hour and 2 hour

Question 14

Treating type 1 diabetes

Answer 14

Aim: Mimic normal daily insulin secretion

Endogenous insulin secretion normally peaks within one hour after a meal with insulin secretion and plasma glucose levels returning to basal levels within two hours of the end of the meal induced hyperglycaemia

Question 15

Insulin treatment regimes

Answer 15

Premixed insulin

• requires less injecting
• timing of meals may be critical

Insulin and food taken at the same time

• greater flexibility for those doing shift work
• potential nocturnal hypoglycaemia

Rapid acting with short half life

• reduces potential for nocturnal hypoglycaemia
• more expensive

Question 16

Type 2 non insulin dependent diabetes

Answer 16

Not enough insulin to keep the blood glucose normal

Combination of

• impaired insulin secretion
• increased peripheral insulin resistance
• increased hepatic glucose output

Insensitivity of target cells to insulin

Link to obesity

Glucagon secretion not increased

Question 17

Mechanisms of insulin resistance

Answer 17

Mutations in insulin receptor gene (very rare)

Defects in insulin signalling pathway

Include defects in cellular translocation of Glut-4 (observed in obesity and diabetes)

Peripheral insulin resistance induced by presence of excess fatty acids- inhibit peripheral glucose disposal and enhance hepatic glucose output

Question 18

Features of type 2 diabetes

Answer 18

Develops over man years

May be up to 90% diabetic population

Survive long term without insulin and often older and obese

Associated with macrovascular disease, stroke and atherosclerosis

Incidence in Japan increasing with western diet

May be asymptomatic, but may have classic hyperglycaemic symptoms

Ketone bodies present n low concentrations

Question 19

Metabolism in type 2 diabetes

Answer 19

Glucagon levels not raised to same extent as type 1, some insulin present and suppresses glucagon secretion

Hyperglycaemia arises from lack of glucose uptake

Uncontrolled lipolysis and therefore ketone body formation not features of type 2 as insulin release suppresses glucagon secretion

Hypertriglyceridaemia and macrovascular disease due to increased VLDL synthesis in liver

Question 20

Treatment of type 2

Answer 20

Diet and exercise

Oral hypoglycaemic agents- various therapeutic targets

Insulin secretion e.g. sulphonylureas

Tissue insulin sensitvity e.g. biguanides

Absorption and digestion of carbohydrates e.g. glucosidase inhibitors

Question 21

Sulphonylureas

Answer 21

Glucose depolarises the membrane by ATP dependent closing of K+ channels

Depolarisation of the membrane opens voltage-dependent Ca2+ channels with influx of Ca2+ causing secretion

Sulphonylureas interact with receptor closing K+ channel

Question 22

Metformin

Answer 22

1St choice hypoglycaemic agent

Does not produce hypoglycaemia

Suppresses appetite- useful if overweight

Only effective in the presence of insulin

Increases insulin sensitivity

Reduces LDL and VLDL and CV risk

Question 23

Thiazolidinediones

Answer 23

Slow onset, effect achieved after 1-2 months of treatment

Reduces hepatic glucose output and increase glucose uptake into muscle, enhances effectiveness of endogenous insulin and reduces amount of exogenous insulin needed

Reduction in glucose may be accompanied by reductions in circulating insulin, free fatty aids, triglycerides and small dense LDL particles

Bind to nuclear receptor, the peroxisome proliferator activator receptor -y regulating gene expression, particularly in adipose tissue

Question 24

GLP-1 and GIP targeting

Answer 24

Produced by endocrine cells of intestine following ingestion of food and stimulate insulin secretion

Have very short half life in vivo so ineffective as therapeutic

Question 25

Exendin-4

Answer 25

39 amino acid peptide hormone found in the saliva of the poisonous gila monster

Powerful stimulator of GLP 1 receptor

Question 26

Exenatide

Answer 26

Synthetic version of exendin 4 with longer half life in vivo

Stimulates insulin secretion

Inhibits glucagon secretion

Glucose production by the liver

Question 27

Vildagliptin

Answer 27

Inhibits the inactivation GLP-1 and GIP allowing increased activity of GLP-1

Can be used in combination with oral hypoglycaemics

Danger of hypoglycaemia